DE19681420B4 - Device and delivery method for transdermal electrotransport delivery of fentanyl and sufentanil - Google Patents

Abstract

An electrotransport device (10) for administering a total amount of an analgesic drug through a body surface, comprising:
An anodic silver donor electrode (22),
A cathodic counter electrode (24),
A donor reservoir (26) containing a loading amount of an analgesic drug in electrical contact with the donor electrode (22), the analgesic drug being a salt of an active agent selected from the group consisting of fentanyl and fentanyl analogs, and
An electronic circuit that controls the delivery of the analgesic drug by applying an electrotransport current,
wherein the device (10) is adapted to deliver a total amount of the analgesic drug required to induce and maintain the analgesia over a period of time that is at least two times greater than the total amount required to induce and maintain analgesia, a transient discoloration of the epidermis to prevent.

Description

TECHNICAL AREA

The This invention relates generally to improved electrotransport drug delivery. Specifically, the invention relates to a device, a composition and a method for an improved electrotransport delivery of analgesic drugs, in particular of fentanyl and analogs of fentanyl.

STATE OF THE ART

The transdermal delivery of drugs by diffusion through the Epidermis offers improvements over more traditional delivery methods, such as subcutaneous injections and oral delivery. A transdermal Drug delivery avoids the hepatic first-pass effect, one encounters with oral drug delivery. A transdermal Drug delivery also eliminates those with subcutaneous injections associated inconvenience for the patient. additionally For example, transdermal delivery may provide more uniform drug concentrations in the patient's bloodstream cause the time due to the extended controlled release profiles certain types of transdermal delivery devices. The term "transdermal" delivery includes all generally the delivery of an agent through a body surface, such as the skin, mucosa or Nails one Animal.

The Skin acts as a primary Barrier for The transdermal penetration of substances into the body and provides the main resistance of the body for the transdermal delivery of therapeutic agents, such as drugs today, the efforts have focused on reducing physical resistance or the permeability the skin for to increase the delivery of drugs through passive diffusion. Various Procedure for increasing the rate of transdermal drug flux has been attempted especially using chemical flux enhancers were.

Other Strategies to reduce the rates of transdermal drug delivery to increase, include the use of alternative energy sources, such as electrical Energy and ultrasound energy. Electrically assisted transdermal Delivery is also known as electrotransport. The term "electrotransport" as used herein refers generally to the delivery of an agent (eg Drug) through a membrane, such as skin, mucosal membranes or nails. The delivery is induced or assisted by the application of an electrical current Potential. For example, a salutary therapeutic agent through an electrotransport delivery through the skin into the large circulation of a human body introduced become. A widely used electrotransport process, electromigration (also referred to as iontophoresis) includes the electrically induced Transport of charged ions. Another type of electrotransport, Electro-osmosis, included the flow of a Liquid, being the liquid contains the means to be dispensed under the influence of an electric Field. Yet another type of electrotransport process, electroporation, comprises the formation of temporary existing pores in a biological membrane by the application an electric field. A remedy can be through the pores either passive (ie without electrical assistance) or active (ie under the influence of a electrical potential) are delivered. However, everyone can electrotransport processes more than one of these methods including at least to a certain extent at "passive" diffusion at the same time to a certain extent. Accordingly, the term "electrotransport" should be used here will, the widest possible Experience interpretation so that he the electrically induced or enhanced transport of at least an agent that can be charged, uncharged or a mixture thereof can, includes independently from the special mechanism or mechanisms, by which the agent is transported on a case-by-case basis.

Electrotransport devices Use at least two electrodes that are in electrical contact with a section of the skin, the nail, a mucous membrane or another body surface. An electrode, usually referred to as "donor" electrode is, is the electrode from which the agent is released into the body becomes. The other electrode, typically referred to as a "counter" electrode is used to power the electrical circuit through the body shut down. For example, if the agent to be delivered is positively charged, d. H. a cation, then the anode is the donor electrode, while the Cathode is the counter electrode that completes of the circuit is used. Alternatively, if an agent is negatively charged is, d. H. an anion, the cathode is the donor electrode and the Anode is the counter electrode. In addition, both the anode and the cathodes are considered to be donor electrodes when ions are both anionic as well as cationic agent or uncharged dissolved agents to be delivered.

Moreover, electrotransport delivery systems generally require at least one reservoir or a source of the agent to be delivered to the body. Examples of such donor reservoirs include a pocket or void, a porous sponge or porous pad, and a hydrophilic polymer or gel matrix. Such donor reservoirs are electrically connected to and interposed between the anode or cathode and the body surface to provide a fixed or renewable source of one or more agents or drugs. Electrotransport devices also have an electrical power source, such as one or more batteries. Typically, one pole of the current source is electrically connected to the donor electrode at all times, while the opposite pole is electrically connected to the counter electrode. Since the rate of electrotransport drug delivery has been shown to be approximately proportional to the electrical current applied by the device, many electrotransport devices typically have an electrical control unit that controls the voltage and / or current applied by the electrodes. which controls the rate of drug delivery. These control circuits use various electrical components to control the amplitude, polarity, timing, waveform shape, etc. of the electrical current and / or the voltage supplied by the power source. See, for example, McNichols et al., US 5 047 007 A ,

To date, commercially sold transdermal electrotransport drug delivery devices have generally employed an electrical desktop power supply unit and a pair of skin contacting electrodes. The donor electrode contains a drug solution while the counter electrode contains a solution of a biocompatible electrolyte salt. The power supply unit has electrical adjusters to adjust the level of the electrical current applied by the electrodes. The "satellite" electrodes are connected to the electrical power supply unit by long (eg 1-2 meters), electrically conductive wires or cables, the wire connections can be interrupted and restrict the movements and mobility of the patient Electrodes and adjusters may also be troublesome and inconvenient for the patient Other examples of desktop electric power supply units using "satellite" electrode assemblies are disclosed in Jacobsen et al. US 4 141 359 A (please refer 3 and 4 ), LaPrade, US 5,006,108 A (please refer 9 ), and Maurer et al., US 5,254,081 A disclosed.

Recently, small independent electrotransport dispensers have been proposed to be worn on the skin, sometimes unobtrusively under clothing, for extended periods of time. Such small independent electrotransport dispensers are used, for example, in Tapper, US 5,224,927 A , Sibalis et al., US 5 224 928 A and Haynes et al. US 5 246 418 A , disclosed. WO 93/01807 A1 describes an independent transdermal drug delivery system that has both an active drug reservoir that delivers a drug by iontophoresis and a passive drug reservoir that delivers a drug by diffusion. In one example, a system for transdermal delivery of fentanyl and in another example, a system for transdermal delivery of sufentanil is provided. The document also describes a number of prior patents and publications relating to passive and iontophoresis-based transdermal drug delivery systems.

Recently, there have been proposals to use electrotransport devices having a reusable control unit adapted for use with a plurality of drug-containing units. The drug-containing units are simply disconnected from the control unit when the drug is depleted, and thereafter, a fresh drug-containing unit is connected to the control unit. In this way, the relatively more expensive hardware components of the device (eg, batteries, LED diodes, circuit hardware, etc.) may be included in the reusable control unit and the relatively less expensive donor reservoir and counter reservoir matrices may be present in the drug contained disposable or disposable unit, whereby the total cost of the electrotransport drug delivery can be reduced. Examples of electrotransport devices comprising a reusable control unit removably connected to a drug containing moiety are described in Sage, Jr., et al. US 5 320 597 A , Sibalis, US 5,358,483 A , Sibalis et al., US 5 135 479 A ( 12 ), and Devane et al. GB 2 239 803 A disclosed.

at the advancement of electrotransport devices Hydrogels for a use as a drug and electrolyte reserve matrix particularly preferred, in part due to the fact that water the preferred liquid solvent for one Use in electrotransport drug delivery is due of its excellent biocompatibility or biocompatibility in comparison to other liquid ones Solvents like alcohols and glycols. Hydrogels have a high equilibrium water content and can Absorb water quickly. additionally Hydrogels tend to have good biocompatibility across from the skin and opposite Mucous membranes.

From Of particular interest in transdermal delivery is delivery analgesic drug for the treatment of moderate to severe pain. A control of the rate and duration of drug delivery is especially important for the transdermal delivery of analgesic drugs to the potential Risk of overdose and to avoid the inconvenience of insufficient dosage.

A Class of analgesics used in a transdermal delivery route have found the synthetic opiates, a group of 4-aniline piperidines. The synthetic opiates, z. Fentanyl and certain of its derivatives, like Sufentanil, are for a transdermal administration is particularly well suited. These synthetic ones Opiates are due to the rapid onset of analgesia, which is highly effective and the short duration of action. They are called 80- resp. 800 times more effective than morphine. These medicines are weak bases, d. H. Amines, of which the main part in acidic media is cationic.

In an in vivo plasma concentration study, Thysman and Preat (Anesth., 77: 1993, 61: 66) compared the facile diffusion of fentanyl and sufentanil with electrotransport delivery in citrate buffer at pH 5. The simple Diffusion produced no detectable plasma concentration. The achievable plasma concentrations depended on the maximum flux of drug that can pass through the skin and on the pharmacokinetic properties of the drug, such as clearance and volume of distribution. Electrotransport delivery was reported to have a significantly reduced lag phase (ie, the time required to reach peak plasma levels) compared to passive transdermal patches (1.5 h vs 14 h). The researchers concluded that electrotransport of these analgesic drugs may allow for more rapid control of pain than traditional patches, and that pulsed drug release (by controlling electrical current) was comparable to constant delivery of classical patches. See also z. Thysman et al., Int. J. Pharm., 101 (1994), pp. 105-113, V. Préat et al., Int. J. Pharm., 96 (1993), pp. 189-196 (sufentanil), Gourlav et al., Pain, 37 (1989), pp. 193-202 (fentanyl), Sebel et al., Eur. J. Clin , Pharmacol. 32 (1987), pp. 529-531 (fentanyl and sufentanil). Passive, ie by diffusion, and electrically assisted transdermal delivery of narcotic analgesic drugs, such as fentanyl, for inducing analgesia have also both been described in the patent literature. See, for example, Gale et US 4,588,580 B1 , and Theeuwes et al., US 5 232 438 B1 ,

In The last few years have been postoperative in terms of treatment Pain is arousing interest in delivery systems other than electrotransport delivery directed. Special attention is given to devices and systems which, within predetermined limits, it has been turned Enable patients control the amount of analgesic that the patient receives. With These types of devices have generally been the experience that the Control of administration of analgesics by the patient to the Administration of fewer analgesics to the patient, as would have been administered if the dosage has been prescribed by a doctor. A Self-administered or patient-controlled self-administration is as patient-controlled or patient-controlled analgesia (PCA; patient-controlled analgesia ") become (and is referred to here as such).

Known PCA devices are typically electromechanical pumps requiring large capacity, electrical power sources, e.g. As alternating current or a plurality of battery packs with large capacity, which are bulky. Because of their size and complexity, commercially available PCA devices generally require the patient to remain tied to a bed or other substantially fixed location. Known PCA devices administer drugs to the patient via an intravenous line or catheter that must be introduced into the target vein, artery, or other target organ by qualified medical personnel. This technique requires that the skin barrier be broken to administer the analgesic. (See Zdeb, US 5 232 448 A ). Accordingly, PCA, as practiced using commercially available PCA devices, requires the presence of highly skilled medical personnel to begin and monitor the operation of the PCA device, as well as the associated risk of infection. Further, commercially available PCA devices themselves are only to be used with some pain due to their percutaneous (ie, intravenous or subcutaneous) access.

From the US 5,203,768 A For example, there is known a transdermal drug delivery device having an active and a passive drug reservoir. The active reservoir is for administration of the drug by iontophoresis, while the passive reservoir is for administration by diffusion. The drug in the active reservoir may comprise a fentanyl or sufentanil salt.

US 5 320 731 A discloses an iontophoretic device for transcutaneous administration of a Active substance comprising electrodes, of which at least one has an electrochemically degradable material. The amount of this degradable material corresponds to the amount of electricity required to administer the given total amount of active ingredient.

Of the The state of the art has little in the direction of transdermal electrotransport devices spawned with the her conventional PCA devices in terms of the amount of drug used to achieve adequate analgesia and administered in a patient-controlled manner, can compete. Further, little progress has been made to form a hydrogel formulation for one Electrotransport of analgesics, especially a transdermal Electrotransport delivery of fentanyl, which has long-term stability and performance characteristics consistent with those provided by the patient controlled electromechanical pumps z. For intravenous delivery of analgesics. There is a need to provide an analgesic formulation in a suitable device, to take advantage of the convenience of an electrotransport levy in a small, independent, to pull through the patient-controlled device.

DESCRIPTION OF THE INVENTION

The The invention provides a device for improved transdermal Electrotransport delivery of fentanyl and fentanyl analogs, in particular Sufentanil, ready. As such, the device of the invention stops greater degree of efficiency in electrotransport delivery of analgesic fentanyl or Sufentanil ready, while providing a greater degree of safety and comfort for the Patients in the treatment of pain is possible. The mentioned and other advantages of the invention are provided by an electrotransport delivery device for delivery of fentanyl or sufentanil through a body surface (e.g. intact skin) provided by electrotransport, the device having a anodic silver donor electrode, a cathodic counter electrode, a donor reservoir containing a loading amount of an analgesic drug contains in electrical contact with the donor electrode, the analgesic Drug is a salt of an active substance that consists of fentanyl and Fentanyl analogs selected is, and an electronic circuit, the delivery of the analgesic by controlling an electrotransport current. The device is adapted to induce and maintain the analgesic required total amount of the analgesic drug over a Period. The load is twice as high as which is required to induce and maintain analgesia Total to a temporary discoloration to prevent the epidermis. The anodic donor reservoir contains a at least partially aqueous solution of a fentanyl / sufentanil salt. Furthermore, the invention provides a method of providing such an electrotransport delivery device prepared by the penetration of an amount of fentanyl or Sufentanilhalogenids is characterized in the reservoir, the sufficient, a temporary discoloration to prevent the epidermis and one to induce and maintain give the analgesia required total amount of analgesic.

In the electrotransport device of the invention, a donor reservoir formulation is used for a transdermal electrotransport device for fentanyl / sufentanil delivery comprising a silver-containing anodic donor electrode, the donor reservoir formulation substantially migration of silver ions into the skin of the patient and discoloration thereof prevented. While the prior art has taught the benefit of using a drug halide salt to prevent the migration of electrochemically generated silver ions (see Untereker et al. US 5 135 477 A ), it has now been discovered that for halide salts of fentanyl or sufentanil, delivered either continuously or intermittently over longer electrotransport delivery periods (eg, over periods of at least several hours), the amount of fentanyl / sufentanil halide, the in the donor reservoir needed to prevent this silver migration, must be in substantial excess of the amount of fentanyl / sufentanil required for therapeutic purposes. For fentanyl hydrochloride, it has been found that the amount of drug needed to prevent silver ion migration is at least about three times the amount needed for delivery to the patient, at least under the particular electrotransport delivery conditions ( ie, charged electrotransport current, reservoir size / weight / composition, and electrotransport stream loading time), which are described in more detail below.

Other Benefits and a more complete appreciation special adjustments, composition variations and physical Features of the invention can from an exam the following drawings, the detailed description, the examples and the attached claims be removed.

BRIEF DESCRIPTION OF THE DRAWING

The The invention will be described below in conjunction with the accompanying drawings described in the:

1 an exploded perspective view of an electrotransport drug delivery device according to the invention is.

WAYS OF CARRYING OUT THE INVENTION

The The invention relates generally to improved transdermal devices Electrotransport delivery of fentanyl or sufentanil in the form of water-soluble Salts to achieve a systemic analgesic effect. there is the fentanyl or sufentanil halide donor reservoir composition adapted to the electrotransport dispenser to be used with an anodic silver donor electrode, wherein the formulation is effective, discoloration of the skin by silver ions, the while formed the oxidation of the silver anode and together with the drug be delivered into the skin of the patient.

Since fentanyl and sufentanil are both bases, the salts of fentanyl and sufentanil are typically acid addition salts, e.g. Citrate salts, hydrochloride salts, etc. The acid addition salts of fentanyl typically have solubilities in water of about 25 to 30 mg / ml. The acid addition salts of sufentanil typically have solubilities in water of about 45 to 50 mg / ml. When these salts are introduced into a solution (eg, an aqueous solution), the salts dissolve to form protonated fentanyl or sufentanil cations and counter (eg, citrate or chloride) anions. As such, the fentanyl / sufentanil cations are administered by the anodic electrode of an electrotransport delivery device. Anodic silver electrodes have been proposed for transdermal electrotransport delivery as a way of maintaining pH stability in the anodic reservoir. See, for example, Untereker et al. US 5 135 477 A , and Petelenz et al. US 4,752,285 B1 , These patents also mention one of the disadvantages of using an anodic silver electrode in an electrotransport delivery device, namely that the application of current through the silver anode causes the silver to be oxidized (Ag → Ag ⁺ + e ^- ), forming silver cations, which compete with the cationic drug for delivery into the skin by electrotransport. Migration of silver ions into the skin results in a transient discoloration of the epidermis ("transient epidermal discoloration" (TED)) of the skin. In addition to these patents, Phipps et al. WO 95/27350 A1 the use of additional chloride ion sources in the form of high molecular weight chloride resins in the donor reservoir of a transdermal electrotransport delivery device. Although these resins are highly effective in providing sufficient chloride to prevent migration of silver ions and the associated skin discolorations, these resins may also have adverse reactions with either the drug to be delivered (ie, drug binding to the resin) and / or with the skin of the patient (ie contributing to skin irritation reactions). Accordingly, for purposes of the following discussion, it is believed that the donor reservoir formulations of the invention are substantially free of such resins as secondary chloride ion sources. Of course, during operation of a transdermal electrotransport device, chloride ions from the patient's body will migrate from the skin to the anodic reservoir. This inherent phenomenon also occurs during operation of the devices of the invention, and as such, the chloride exiting the skin to the donor anodic reservoir is not considered to be an "additional source of halide / chloride ion" in the sense that the term is used herein. While the patents to Untereker and Petelenz teach that by providing a cationic drug in the form of a halide salt, migration of silver ions is prevented (ie, by reacting the silver ions with the halide counterion of the drug to form a water-insoluble silver halide precipitate; ⁺ + X ^- → AgX), it has now been found that a considerable excess (ie, an amount which is in substantial excess over the fentanyl halide salt which must be delivered to the patient for the purpose of achieving analgesia) of fentanyl halide in one Donor Reservoir of a Fentanyl Elek trotransport delivery device must be provided to prevent silver ion migration. This is especially true for those transdermal electrotransport delivery devices that are adapted to provide an electrotransport current for extended periods of time, e.g. B. longer than about 6 hours to apply.

In general, the "excess" amount of fentanyl halide needed to prevent silver ion migration will depend largely on a number of factors, including the particular halide salt used (eg, chloride, fluoride, bromide, or iodide salt of the drug), the level of applied electrotransport current, size / weight / composition of the donor reservoir, the value of the applied current density and the time duration over which the electrotransport current is applied. We have determined, for delivery of fentanyl hydrochloride from polyvinyl alcohol donor reservoirs used to deliver fentanyl for periods of up to about 15 hours, that the amount of fentanyl HCl required to transport silver ions during electrotransport About 2 to 3 times the amount of fentanyl HCl, based on the amount needed for delivery to the patient over the same period for the purposes of inducing and maintaining analgesia.

In the specific case of an electrotransport delivery device having a donor reservoir based on polyvinyl alcohol containing fentanyl hydrochloride and having a total weight (on a hydrated basis) of about 0.3 to 0.8 g, the device (1) comprising a silver ( For example, silver foil or silver powder-loaded polymeric film containing anodic donor electrode in electrical contact with the donor reservoir has (2) an electrical current source connecting the donor and counter electrodes with a DC or DC current of approximately 190 μA to 230 μA, (3) has a current density, measured as the total applied current divided by the skin contact area of the donor reservoir, of less than about 0.3 mA / cm ² applied and (4) capable of applying such current for up to about eighty separate dispensing intervals of about 8 to about 12 minutes duration is that for inducing and opening whereas fentanyl-HCl loading required for analgesia is about 2.5-3.5 mg, whereas the fentanyl-HCl loading required to prevent TED is at least about 8-10 mg, and preferably at least about 11-13 mg , Specifically in the case of an electrotransport delivery device having a donor reservoir based on polyvinyl alcohol containing fentanyl hydrochloride and having a total weight (on a hydrated basis) of about 0.5 to 0.8 g, the device comprising the electrodes with a GS or DC current of about 210 μA and capable of delivering such current for up to about eighty separate delivery intervals of about 10 minutes duration is the fentanyl-HCl loading required to induce and maintain analgesia , about 3 mg, whereas the fentanyl-HCl loading required to prevent TED is at least about 9 mg, and preferably at least about 12 mg.

Around the loading of a different halide salt of fentanyl as Determining fentanyl HCl is only required an equivalent molar amount of halide ions to the reservoir, since the silver halide salts have a fairly uniform low water solubility exhibit. For example, the loading is from 8 to 10 mg Fentanyl HCl at a molar loading of about 20 to 25 μmol. Accordingly be about 20 to 25 μmol any other of the fentanyl halides (eg fentanyl fluoride, Fentanyl bromide or fentanyl iodide) a similar extent Prevent silver migration such as fentanyl HCl.

In addition to Fentanyl may contain "excess" amounts of sufentanil halide salts also be used to a migration of silver ions to prevent. Because sufentanil about 7 to 10 times more effective than Fentanyl is only about that 0.1 to 0.14 times the fentanyl dose required to obtain an equivalent Extent To achieve analgesia. However, because the transdermal electrotransport delivery efficiency of sufentanil (ie the rate at which sufentanil per unit of applied electrotransport stream is delivered) only about one third that of fentanyl is the charged electrotransport current, which is required to the same extent of analgesia with sufentanil to achieve about 0.3 to 0.4 times that needed for fentanyl. Accordingly, the "excess" amount of sufentanil chloride, which needed to silver ion migration during electrotransport delivery of sufentanil accordingly, to about 6 to 10 μmol or approximately 2.4 to 4 mg reduced. The amount of sufentanil HCl loading that needed is to prevent silver ion migration, based on the Loading that needed in order to achieve an analgesic effect in a patient, is at least that about 4 times the analgesic loading.

As long as the reservoir matrix material has substantially no silver ion binding capacity (ie, by means of fixed anionic (eg, COO ^-.) Groups, such as are found in cation exchange membranes), has the respective than Donorreservoirmatrix selected matrix material, if at all only a slight effect on the minimum loading of Halide salts of fentanyl and sufentanil, which is effective to prevent silver ion migration into the skin of the patient. In particular, hydrogel matrices show little or no tendency to bind silver ions and, accordingly, are a preferred matrix material for use in this aspect of the invention.

Preferably, the concentration of fentanyl or sufentanil in solution in the donor reservoir is maintained at or above a concentration at which the transdermal fentanyl / sufentanil electrotransport flux exits depends on the drug concentration in the donor reservoir. The transdermal fentanyl electrotransport flux begins to become dependent upon the concentration of the fentanyl salt in aqueous solution when the fentanyl salt concentration falls below about 11 to 16 mM.

The Concentration of 11 to 16 mM is only based on the volume from liquid Solvent that is used in the donor reservoir, and not based on the Total volume of the reservoir calculated. In other words, the concentration includes from 11 to 16 mM does not increase the volume of the reservoir passing through the Reservoir matrix material (eg hydrogel or other matrix material) is pictured. Furthermore For example, the concentration of 11 to 16 mM is based on the number of moles Fentanyl salt and not on the equivalent Number of moles of free fentanyl base contained in the donor reservoir solution. For fentanyl HCl the concentration of 11 to 16 mM corresponds to about 4 to 6 mg / ml. Other fentanyl halide salts become slightly less have different concentration ranges based on the weight based on the difference in molecular weight of the counterion of respective eligible fentanyl salt. If the fentanyl salt concentration at about 11 to 16 mM drops, the transdermal fentanyl electrotransport flux begins to decrease significantly, even when the applied electrotransport current remains constant. Around a predictable fentanyl flux at a certain level ensure the applied electrotransport stream is accordingly, the fentanyl salt concentration in the donor reservoir contained solution preferably over approximately 11 mM, and more preferably above about 16 mM held. additionally to fentanyl also have water-soluble Salts of sufentanil Minimum concentrations in aqueous solution, among which the transdermal Electric transport flow dependent on the concentration of Sufentanilsalzes in solution. The minimum concentration for sufentanil is approximately 1.7 mM.

The The invention provides an electrotransport dispenser for dispensing of fentanyl or sufentanil through a body surface, e.g. B. skin to an analgesic To make an impact, ready. The fentanyl or sufentanil salt becomes preferably in a donor reservoir of an electrotransport delivery device provided as an aqueous saline solution.

The Fentanyl dose delivered by transdermal electrotransport is, is preferably about 20 μg to approximately 60 μg over one Delivery period of up to about 20 min in human patients with a body weight of 35 kg or more. More preferred is a dosage of from about 35 μg to about 45 μg, and most preferred a dosage of about 40 μg for the delivery period. The device of the invention preferably further comprises means to giving up about 10 to 100 and more preferably about 20 to 80 additional similar ones Cans over a period of 24 hours to achieve the analgesic effect and uphold.

The Sufentanil dose given by transdermal electrotransport is, is preferably about 2.3 μg to approximately 7.0 μg over one Delivery period of up to about 20 min in human patients with a body weight of 35 kg or more. More preferred is a dosage of from about 4 μg to about 5.5 μg, and most preferred a dosage of about 4.7 μg for the delivery period. The Device of the invention comprises further preferably, means for dispensing from about 10 to 100, and more preferably approximately 20 to 80 additional similar Cans over a period of 24 hours to achieve the analgesic effect and uphold.

The formulation in the fentanyl / sufentanil salt-containing anodic reservoir for transdermal delivery of the above-noted doses of fentanyl / sufentanil by electrotransport preferably comprises an aqueous solution of a water-soluble fentanyl / sufentanil salt, such as HCl salt. Most preferably, the aqueous solution is contained within a hydrophilic polymer matrix, such as a hydrogel matrix. The fentanyl / sufentanil salt is present in an amount sufficient to deliver the above indicated doses transdermally by electrotransport over a delivery period of up to about 20 minutes to achieve a systemic analgesic effect. The fentanyl / sufentanil salt typically constitutes about 1 to 10 weight percent of the fully hydrated base donor reservoir formulation (including the weight of the polymeric matrix), and more preferably about 1 to 5 weight percent of the fully hydrated base donor reservoir formulation. Although not critical to the invention, the applied electrotransport current density is typically in the range of about 50 to 150 μA / cm ² and the applied electrotransport current typically in the range of about 150 to 240 μA.

The anodic fentanyl / sufentanil salt-containing hydrogel may suitably be made of any of a variety of materials, but preferably comprises a hydrophilic polymeric material, preferably one that is polar in nature to enhance drug stability. Suitable polar Polymers for the hydrogel matrix include a variety of synthetic and naturally occurring polymeric materials. A preferred hydrogel formulation contains a suitable hydrophilic polymer, a buffer, a humectant, a thickening agent, water, and a water-soluble fentanyl or sufentanil salt (e.g., HCl salt). A preferred hydrophilic polymer matrix is polyvinyl alcohol, for example, a washed and fully hydrolyzed polyvinyl alcohol (PVOH). A suitable buffer is an ion exchange resin which is a copolymer of methacrylic acid and divinylbenzene and is in both an acid and a salt form. An example of such a buffer is a mixture of polacrilin (copolymer of methacrylic acid and divinylbenzene, and the potassium salt thereof A mixture of the acid and potassium salt forms of polacrilin acts as a polymeric buffer to adjust the pH of the hydrogel to about pH 6. Use of a humectant in the hydrogel formulation is useful to inhibit the loss of moisture from the hydrogel An example of a suitable humectant is guar gum Thickening agents are also useful in a hydrogel formulation For example, a polyvinyl alcohol thickener such as hydroxypropyl methylcellulose (e.g. Methocel K100MP, available from Dow Chemical, Midland, MI), helps to modify the rheology of a hot polymer solution when it is filled into a mold or cavity The hydroxypropyl methylcellulose increases in viscosity on cooling and reduces the tendency of a cooled one Polym redemption significantly overfill the mold or cavity.

In a preferred embodiment comprises the anodic fentanyl / sufentanil salt-containing hydrogel formulation approximately 10 to 15 wt .-% polyvinyl alcohol, 0.1 to 0.4 wt .-% resin buffer and about 1 to 2% by weight of fentanyl or sufentanil salt, preferably the hydrochloride salt. The remainder are water and ingredients such as humectants, thickeners, u. s. w. The polyvinyl alcohol (PVOH) based hydrogel formulation is manufactured by using all materials including the Fentanyl or sufentanil salt in a single vessel at elevated temperatures of about 90 ° C to 95 ° C for at least about 0.5 h be mixed. The hot one Mixture is then poured into foam molds and at freezing temperature from about -35 ° C over night stored to crosslink the PVOH. When heated to room temperature a tough one obtained elastomeric gel for an electrotransport of fentanyl is suitable.

The hydrogel formulations are used in an electrotransport device as described below. A suitable electrotransport device comprises an anodic donor electrode, preferably containing silver, and a cathodic counter electrode, preferably containing silver chloride. The donor electrode is in electrical contact with the donor reservoir containing the aqueous solution of a fentanyl / sufentanil salt. As described above, the donor reservoir is preferably a hydrogel formulation. The counter reservoir also preferably comprises a hydrogel formulation containing a (eg, aqueous) solution of a biocompatible electrolyte, such as citrate buffered saline. The anodic and cathodic hydrogel reservoirs preferably each have a skin contact area of about 1 to 5 cm ^2, and more preferably about 2 to 3 cm ² . The anodic and cathodic hydrogel reservoirs preferably have a thickness of about 0.05 to 0.25 cm, and more preferably about 0.15 cm. The applied electrotransport current is about 150 μA to about 240 μA, depending on the desired analgesic effect. Most preferably, the applied electrotransport stream is a substantially constant DC or DC stream during the metering interval.

It will now be related to the 1 which shows an exemplary electrotransport device that can be used in the present invention. 1 shows an exploded perspective view of an electrotransport device 10 with an activation switch in the form of a push-button 12 and a display in the form of a light emitting diode (LED) 14 ,

The device 10 includes an upper housing 16 , an assembly with a printed circuit 18 , a lower case 20 , an anode electrode 22 , a cathode electrode 24 , an anode reservoir 26 , a cathode reservoir 28 and a skin-friendly adhesive 30 , The upper case 16 has side wings 15 that contribute to the device 10 to hold on the skin of a patient. The upper case 16 is preferably formed from an injection moldable elastomer (e.g., ethylene vinyl acetate). The assembly with the printed circuit 18 includes an integrated circuit 19 that with discrete electrical components 40 and a battery 32 is coupled. The assembly with the printed circuit 18 is on the case 16 by cones (in 1 not shown) through openings 13a and 13b go through, with the ends of the pins are heated or melted to the printed circuit board assembly 18 with the housing 16 put together hot. The lower case 20 is on the upper case 16 by means of the adhesive 30 attached, with the upper surface 34 of the adhesive 30 both to the lower case 20 as well as the upper case 16 including the down-facing surfaces of the wings 15 adheres.

On the bottom of the printed circuit board assembly 18 (partially) shown is a battery 32 , which is preferably a coin cell battery, and most preferably a lithium cell. Other types of batteries may be used to power the device 10 be used with energy as well.

The circuit outputs (in 1 not shown) of the printed circuit board assembly 18 make electrical contact with the electrodes 24 and 22 through openings 23 . 23 ' in the wells 25 . 25 ' , which are formed in the lower housing, by means of electrically conductive adhesive strips 42 . 42 ' ago. The electrodes 22 and 24 in turn, they are in direct mechanical and electrical contact with the topsides 44 ' . 44 from reservoirs 26 and 28 , The subpages 46 ' . 46 the reservoirs 26 . 28 touch the skin of the patient through the openings 29 ' . 29 in the glue 30 , After depressing the push-button 12 supplies the electronic circuit on the printed circuit board assembly 18 a predetermined DC or DC current to the electrodes / reservoirs 22 . 26 and 24 . 28 for a delivery interval of predetermined length, e.g. B. about 10 min. Preferably, the device communicates to the user a visual or audible confirmation of the beginning of the drug delivery or bolus interval by means of the LED 14 which is illuminated, and / or by means of an acoustic sound signal of z. Then, an analgesic drug, such as fentanyl, is passed through the patient's skin, eg, on the arm, for the predetermined (e.g. In practice, a user receives feedback regarding the onset of the drug delivery interval by visual (LED 14 is lit) and / or audible signals (a beep or honk from the "beeper").

The anodic electrode 22 preferably contains silver and the cathodic electrode 24 preferably contains silver chloride. Both reservoirs 26 and 28 preferably contain polymer hydrogel materials as described herein. The electrodes 22 . 24 and reservoirs 26 . 28 be through the lower case 20 retained. For fentanyl and sufentanil salts, the anodic reservoir is 26 the "donor" reservoir containing the drug and the cathodic reservoir 28 contains a biocompatible electrolyte.

The push button switch 12 , the electronic circuit on the circuit board with the printed circuit 18 and the battery 32 are stuck between the upper case 16 and the lower case 20 "Sealed." The upper case 16 preferably contains a rubber material or other elastomeric material. The lower case 20 preferably contains a sheet-like plastic or elastomeric material (e.g., polyethylene) that readily forms depressions 25 . 25 ' shaped and for the formation of openings 23 . 23 ' can be cut. The assembled device 10 is preferably water resistant (ie splash resistant) and most preferably waterproof. The system has a small cross-section that adapts easily to the body, allowing freedom of movement at and around the wearer's seat. The anode / drug reservoir 26 and the cathode / salt reservoir 28 are on the skin contacting side of the device 10 are isolated and sufficiently separated to prevent inadvertent electrical shorting during normal handling and use.

The device 10 adheres to the body surface of the patient (eg the skin) by means of a circulating adhesive 30 that a top 34 and a body-touching side 36 having. The adhesive side 36 has adhesive properties that make sure the device 10 remains in place on the body during normal user activity, yet allows a reasonable distance after the predetermined wearing period (e.g., 24 hours). The upper side of the adhesive 34 adheres to the lower housing 20 and holds the electrodes and drug reservoirs within the housing wells 25 . 25 ' back and holds also the lower case 20 attached to the upper housing 16 ,

The push button switch 12 is at the top of the device 10 isolated and is easily operated through clothing. Press the push-button twice 12 within a short period of time, e.g. B. three seconds, is preferably used to the device 10 to activate for drug delivery, thereby reducing the likelihood of unintentional actuation of the device 10 is minimized.

Upon activation by the switch, an audible alarm signals the beginning of drug delivery, at which time the circuit provides a predetermined level of DC or DC current to the electrodes / reservoirs for a predetermined delivery interval (eg, 10 minutes). The LED 14 remains "on" during the delivery interval, indicating that the device 10 is in a mode of active drug delivery. The battery preferably has sufficient capacity to the device 10 continuously apply the predetermined level of DC or DC current for the entire wearing period (eg 24 h).

The invention will be further illustrated by the following examples, which illustrate the invention, but not limit the scope of the invention.

EXAMPLE 1

The following study was conducted to determine the amount of fentanyl hydrochloride drug loading required to prevent silver migration resulting in transient staining of the epidermis from a fentanyl transdermal electrotransport delivery device with a donor reservoir gel of approximately 0.6 g and has a skin contact area of about 2.8 cm ² , the device being worn for a period of up to 24 hours and having an electrotransport current of 240 μA (i.e., a current density of 87 μA / cm ² ) over a delivery interval of for approximately 10 minutes to deliver a 40 μg dose and deliver up to 80 such doses over the 24 hour gestation period. As a result, the device has the ability to deliver up to 3.2 mg of fentanyl (80 x 40 μg = 3.2 mg) for therapeutic purposes.

Fentanyl-HCl donor reservoirs based on polyvinyl alcohol (PVOH) hydrogel, each reservoir having a total weight of about 0.15 g, were prepared from the following composition: material Wt .-% water 80.8 PVOH 15.0 Fentanyl HCl 2.0 polacrilin 0.1 0.5 N NaOH 2.1

The materials were mixed in a jacketed beaker at 90 ° C and then 0.15 g aliquots of the liquid gel were filled into foam molds and frozen overnight at temperatures ranging from -15 to -50 ° C. The gels had a disk shape with an area of 1.0 cm ² and a thickness of 1.6 mm.

A silver foil was laminated to a surface of each of the gels to form an anodic donor electrode assembly comprising the silver foil anode and the fentanyl-containing gel reservoir. Counter-electrode assemblies were prepared using similar size PVOH gels containing citrate-buffered saline (pH 4). A cathodic silver chloride electrode (ie, a silver chloride powder-loaded polyisobutylene film) was laminated to a surface of the counter gels. The electrodes were electrically connected to conventionally made current sources which applied a constant DC or DC current of 240 μA (87 μA / cm ² ).

The electrotransport systems were applied to the outside of the upper arms of six male volunteers and worn for a period of 15 hours, which is approximately 10% longer than the maximum time that power is applied by that system (ie, 80 x 10 min = 13, 3 h). Over the 15-hour period of wear, the systems continuously applied power, after which the systems were removed and each subject's arm was carefully examined to determine if transient staining of the epidermis (TED) caused by migration of silver ions formed in the anodic electrode assembly , had occurred. Subjects were re-examined one hour and again 24 hours after removal of the system to confirm the initial TED reading. For all six subjects, no TED occurred at the site of attachment of the anodic electrode assembly. This suggests that a fentanyl-HCl loading of about 1.8 to 2 wt% or about 3 mg in these gels provides a sufficient amount of chloride ion to prevent migration of silver ions formed by oxidation of the silver anode. into the patient's skin over the 15-hour wearing period. Accordingly, an electrotransport system that applies the same level of electrotransport current over a maximum metering period of 13.3 hours will similarly not produce TED, even under conditions of maximum use. The loading of 2% by weight of fentanyl HCl in these donor gel reservoirs based on PVOH can be increased in view of larger reservoirs. Accordingly, for a fentanyl-HCl based PVOH-based donor reservoir having a total weight of about 0.6 g, which reservoir contains essentially no source of chloride ion other than the drug counterions, the fentanyl-HCl loading should be at least about 11 mg (ie 1.8 wt% x 0.6 g = 11 mg), even though the maximum amount of fentanyl that can be released from the device over the 24 hour gestation period is only about 3.2 mg fentanyl. To prevent silver migration in this device under conditions of maximum use, an excess amount of Fenta nyl-HCl are introduced into the anodic donor reservoir, wherein the excess load of about 3 to 4 times the amount based on the amount of fentanyl required for therapeutic purposes corresponds.

In summary stated, the invention provides an improved device for the transdermal electrotransport of water-soluble salts of fentanyl and sufentanil, the device being an anodic silver donor electrode and preferably a hydrogel-based donor reservoir. The electrotransport device is preferably one through the Patient controlled device. The hydrogel formulation contains a Drug concentration sufficient to hike Silver ions to the skin of a wearer to inhibit the electrotransport device and accordingly a temporary discoloration to prevent the epidermis, and an acceptable level of analgesia provide.

Claims (21)

Electrotransport device ( 10 ) for administering a total amount of an analgesic drug through a body surface, comprising: - an anodic silver donor electrode ( 22 ), - a cathodic counter electrode ( 24 ), - a donor reservoir ( 26 ) containing a loading amount of an analgesic drug in electrical contact with the donor electrode ( 22 ), wherein the analgesic drug is a salt of an active agent selected from the group consisting of fentanyl and fentanyl analogs, and - an electronic circuit that controls the delivery of the analgesic drug by applying an electrotransport current, the device ( 10 ) is adapted to deliver a total amount of the analgesic drug required to induce and maintain analgesia over a period of time which is at least two times greater than the total amount required to induce and maintain analgesia to prevent transient discoloration of the epidermis. Contraption ( 10 ) according to claim 1, wherein the donor reservoir ( 26 ) comprises a hydrogel containing an aqueous solution of an analgesic drug selected from the group consisting of fentanyl halide salts and sufentanil halide salts in a loading at least three times higher than the total amount required to induce and maintain analgesia, and wherein the donor reservoir ( 26 ) is substantially free of sources of halide other than the analgesic drug halide salt. Contraption ( 10 ) according to claim 1 or 2, wherein the body surface is skin. Contraption ( 10 ) according to claim 3, wherein the skin is intact human skin and the period of application of an electrotransport stream for delivery of the analgesic drug is at least 6 hours. Contraption ( 10 ) according to any one of claims 1 to 4, wherein the drug concentration in the donor reservoir ( 26 ) is maintained at a concentration at which drug delivery is independent of drug concentration in the donor reservoir. Contraption ( 10 ) according to claim 5 wherein the drug is a solution of fentanyl halide in a loading such that upon delivery of the total amount required to induce and maintain analgesia, the fentanyl salt concentration is still above 11 mM based on the volume of the liquid solvent. Contraption ( 10 ) according to claim 5, wherein the drug is a solution of fentanyl hydrochloride in a loading such that after delivery of the total amount required to induce and maintain analgesia, the fentanyl hydrochloride concentration is still above 4 mg / ml based on the volume of the liquid solvent. Contraption ( 10 ) according to claim 5 wherein the drug is a solution of sufentanil halide in a loading such that upon delivery of the total amount required to induce and maintain analgesia, the sufentanil salt concentration is still above 1.7 mM based on the volume of the liquid solvent. Contraption ( 10 ) according to any one of claims 1 to 8, wherein the applied electrotransport current is in the range between 150 μA and 240 μA. Contraption ( 10 ) according to any one of claims 1 to 8, wherein the applied electrotransport current is in the range between 190 μA and 230 μA. Contraption ( 10 ) according to any one of claims 1 to 10, comprising means for delivering the total amount of analgesic drug required to induce and maintain analgesia in multiple doses. Contraption ( 10 ) according to claim 11, wherein the analgesic drug can be delivered in about 10 to 100 similar dosages. Contraption ( 10 ) according to claim 11, wherein the analgesic drug can be delivered in about 20 to 80 similar dosages. Contraption ( 10 ) according to any of claims 11 to 13, wherein the dosage is over a delivery period of up to about 20 minutes. Contraption ( 10 ) according to any one of claims 11 to 14, wherein the dosages comprise 20 to 60 μg fentanyl. Contraption ( 10 ) according to any one of claims 11 to 14, wherein the dosages comprise about 40 μg of fentanyl. Contraption ( 10 ) according to any one of claims 11 to 14, wherein the dosages comprise 4 to 5.5 μg sufentanil. Contraption ( 10 ) according to one of claims 1 to 7 or 9 to 16, wherein the donor reservoir ( 26 ) has a hydrated weight of from about 0.3 g to 0.8 g and is loaded with at least about 9 mg of fentanyl hydrochloride. Contraption ( 10 ) according to claim 18, wherein an electrotransport stream for delivery of the analgesic drug for up to 80 intervals of about 8 to 12 minutes can be applied. Contraption ( 10 ) according to claim 2, wherein the analgesic drug comprises a sufentanil halide and the loading amount is at least about four times higher than the total amount for transdermal administration. Method for providing an electrotransport delivery device ( 10 ) according to any one of claims 1 to 20, wherein the process is characterized by introducing an amount of the fentanyl halide or sufentanil halide into the reservoir ( 26 ), the loading amount being sufficient to prevent transient staining of the epidermis and to deliver a total amount of analgesic drug required to induce and maintain analgesia.